ROS-responsive injectable hydrogels loaded with exosomes carrying miR-4500 reverse liver fibrosis.

The reversal of liver fibrosis requires effective strategies to reduce oxidative stress and inhibition of hepatic stellate cell (HSC) activation. MiR-4500 regulates pathological angiogenesis and collagen mRNA stability, with the potential to inhibit fibrosis. Herein, we explored the inhibition of HSC activation in vitro by exosomes (Exos) carrying miR-4500 and encapsulated Exos in an intelligent injectable hydrogel with biological activity and reactive oxygen species (ROS) responsiveness for application in oxidative stress environments. Briefly, reversible boronic ester bonds were integrated into gelatin-based hydrogels through dynamic crosslinking of quaternized chitosan (QCS) and 4-carboxyphenylboronic acid (CPBA)-modified gelatin. The QCS-CPBA-Gelatin (QCG) hydrogel scavenged excess ROS from the local microenvironment and released Exos through the dissociation of boronic ester bonds, providing a favorable microenvironment and in situ sustained-release drug delivery system for Exos. The results showed that QCG@Exos hydrogel has biocompatibility, biodegradability, and slow-release ability, which could effectively clear ROS and inhibit HSC activation and pathological angiogenesis in vitro and in vivo. Furthermore, transcriptome analysis suggests that the pharmacological mechanism of the QCG@Exos hydrogel is mainly related to anti-oxidation, anti-angiogenesis, anti-fibrosis processes, and signaling pathways. Thus, our study demonstrates that an intelligently responsive Exos delivery system based on injectable hydrogels is a promising strategy for the treatment of liver fibrosis.